A Unified Approach for the Enantioselective Synthesis of the Brominated Chamigrene Sesquiterpenes

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Title: A Uniﬁed Approach for the Enantioselective Synthesis of the Brominated Cha- migrene Sesquiterpenes

Authors: Alexander J. Burckle; Vasil H. Vasilev; Noah Burns

This is the author manuscript accepted for publication and has undergone full peer review but has not been through the copyediting, typesetting, pagination and proofrea- ding process, which may lead to differences between this version and the Version of Record.

To be cited as: 10.1002/anie.201605722

Link to VoR: http://dx.doi.org/10.1002/anie.201605722 COMMUNICATION

A Unified Approach for the Enantioselective Synthesis of the Brominated Chamigrene Sesquiterpenes

Alexander J. Burckle, Vasil H. Vasilev, and Noah Z. Burns*

Abstract: The brominated chamigrene sesquiterpenes constitute a representative of the simplest members of the brominated large subclass of bromocyclohexane containing natural products, yet chamigrenes, specifically its isomeric natural product no general enantioselective strategy for the synthesis of these small counterparts,   bromochamigrene[3,10,11] (3 and 4, molecules exists. Herein we report a general strategy for accessing Figure 1b). We thus devised a strategy that was capable of this family of secondary metabolites including the enantioselective providing facile access to numerous brominated spirodienes in synthesis of ()-- and ()-ent--bromochamigrene, ()-dactylone, enantioenriched form. and ()-aplydactone. Access to these molecules is enabled by a stereospecific bromopolyene cyclization initiated by the solvolysis of an enantioenriched vicinal bromochloride.

Of the roughly 300 natural products that have been isolated and structurally characterized containing a bromocyclohexane motif (1, Figure 1a),[1a-c] more than 50 are represented by the brominated chamigrene sesquiterpenes (2, Figure 1a). Most members of this family differ in their level of saturation, halogenation, and oxygenation (3–8, Figure 1b). The structural variety within the halogenated chamigrenes is complemented by diverse biological activities, with noteworthy examples including antibacterial,[2] antifungal,[3] antiviral,[4] anthelmintic,[5] and anticancer[6] effects. To date, the total synthesis of (+)-elatol 6 by Stoltz and Grubbs[7a] constitutes the only enantioselective synthesis of a member of the halogenated chamigrene sesquiterpenes. A general enantioselective approach for the synthesis of this class of molecules has yet to be reported.[7b–e] Along these lines, we set out to develop a strategy that would enable rapid construction of the spirocyclic core and thus facilitate elaboration to structurally disparate members of this family of small molecules for further chemical and biological investigations. We were particularly intrigued by the cancer preventive agent dactylone (7)[8] and a related congener, aplydactone (8).[9]

Dactylone has been shown to suppress phenotype expression at non-cytotoxic doses in human lung, colon, and skin tumor cell Figure 1. The halogenated chamigrene sesquiterpenes. a) Ubiquitous lines and therefore holds promise as a molecular tool for bromocyclohexane motif and bromochamigrene skeleton; b) representative anticancer studies.[8c] Dactylone and aplydactone were originally members of the natural product class; c) this approach. isolated from the sea hare Aplysia dactylomela in 1987, however the structure of aplydactone was not disclosed until 2001 with the assistance of X-ray crystallography.[9] In that report, it was We targeted isoprenoid-derived bromocycle 10 that could suggested that 8 may arise from an intramolecular [2 + 2] be rapidly elaborated to the spirocyclic chamigrene core (10 to 9, cycloaddition of 7. Accordingly, we selected dactylone 7 as a Figure 1c), providing a general way of accessing this class of synthetic target with the objective of also interrogating its natural products. While a bromonium-induced carbocationic conversion to aplydactone 8. We hoped this investigation would cyclization would provide a direct means to access candidate shed light on the feasibility of this transformation both in a carbocycles, no enantioselective bromopolyene cyclization protocols have been reported on natural product-relevant biosynthetic and laboratory setting. We were confident that 7 [12] could be obtained directly from its corresponding deoxygenated scaffolds. Cognizant of this methodological gap, we saw an precursor 9. This diene, while not yet having been isolated, is opportunity to use enantioenriched vicinal dihalides as progenitors of bromonium ions. Enantiopure bromonium ions have been previously generated from enantioenriched [*] A. J. Burckle, V. H. Vasilev, Prof. Dr. N. Z. Burns bromohydrin derivatives and have been captured in an intra- and Department of Chemistry, Stanford University intermolecular fashion.[12c,d,13b] However, to our knowledge the 333 Campus Dr., Stanford, CA 94305 (USA) generation and subsequent trapping of an enantioenriched E-mail: [email protected] bromonium ion from a vicinal dihalide has not been reported. Supporting information for this article is given via a link at the end of Recently our laboratory disclosed an enantioselective Schiff the document.

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base catalyzed di- and interhalogenation reaction of allylic With the requisite precursor in hand, we subjected 16 to alcohols, providing access to highly enantioenriched ionizing conditions in basic hexafluoroisopropanol (HFIP)[13] bromochlorides,[14a] dibromides, and dichlorides.[14b-d] We optimistic that an enantiopure non-racemizing bromonium ion hypothesized that subjecting these species to ionizing conditions could be generated and captured by the pendant allylic acetate. could facilitate the generation of an enantioenriched halonium To our delight, the cyclization proceeded smoothly and afforded ion that could be captured intramolecularly for productive bromocarbocycle 17 in 54% yield as a single isolated cyclization (12 to 10 via 11, Figure 1c). diastereomer with near-perfect enantiospecificity (90% ee 17; This plan called for the enantioselective dihalogenation of 96% enantiospecificity). Analogous dibromoalcohols were allylic alcohol 13 (Scheme 1), which can be prepared in one step observed to racemize under the ionizing conditions and were from commercially available geranyl acetate.[15] Using conditions unstable to the deoxygenation conditions. To our knowledge this previously disclosed by our laboratory, (R,S)-Schiff base 14- is the first example of the solvolysis and intramolecular capture catalyzed bromochlorination proceeded in good yield (66%) and of an enantioenriched dihalide. with excellent enantioselectivity (94% ee) on 4.4 g scale to We next sought to elaborate enantioenriched carbocycle deliver bromochloride 15. Two-step deoxygenation[14d] followed 17 to the spirocyclic framework relevant to the brominated by reacylation provided >1 g of bromochloro-geranyl acetate 16. chamigrene sesquiterpenes (Scheme 2). We envisioned that an isoprene Diels–Alder transformation with a corresponding exocyclic enone could provide the desired scaffold. Bromocycle 17 was cleanly dehydrated to the exocyclic olefin[16] with subsequent oxidative cleavage[17] affording ketone acetate 18 in good yield (62% over two steps). Facile elimination of the acetate to the exocyclic enone 19 occurred in the presence of DBU with mild heating, but attempts at its isolation led to rapid formation of unusual hetero- 20 upon concentration and standing. Circumventing isolation of this unstable intermediate, enone 19 was generated in situ and treated with dimethylaluminum chloride and excess isoprene,[18] and the desired Diels–Alder adduct was easily obtained as a 4.3:1 (52% 21 + 12% 22) mixture of separable epimers. Access to these diastereomeric spiroketones served as a convenient diversification point in our synthesis providing access to the doubly unsaturated, isomeric - and ent--bromochamigrenes (4 and 3, respectively). Scheme 1. Enantioselective dihalogenation and key solvolytic bromopolyene Transformation of spiroketones 21 and 22 to their cyclization. Reagents and conditions: a) NBS (1.05 equiv), ClTi(Oi-Pr)3 (1.1 corresponding exocyclic olefins was next required for the equiv), 20 mol % (R,S)-14, hexanes, –20 ˚C, 66%; b) triflic anhydride (1.2 synthesis of ent--bromochamigrene 4 and dactylone 7. An equiv), 2,6-lutidine (2.0 equiv), CH2Cl2, –78 ˚C, 85%; c) L-selectride (5.5 equiv), [19] THF, –78 ˚C to r.t., 58%; d) acetic anhydride (1.0 equiv), 4- initial survey of standard methylenation conditions failed to dimethylaminopyridine (0.05 equiv), triethylamine (1.2 equiv), CH2Cl2, r.t., convert any of the spiroketone (21) to the desired olefin 9. We 94%; e) potassium carbonate (1.5 equiv), hexafluoroisopropanol (0.05 M), r.t., reasoned that failed olefinations were due to the combination of 54%. the extremely hindered neopentyl ketone and the bulkiness of

Scheme 2. Synthesis of (–)- -aplydactone, and (–)-- and (–)-ent--bromochamigrene. Reagents and conditions: a) thionyl chloride (1.5 equiv), triethylamine (5 equiv), CH2Cl2, –196 ˚C to –95 ˚C; b) ruthenium(III) chloride (0.02 equiv), sodium periodate (1.5 equiv), MeCN/CCl4/H2O, r.t., 62% from 17; c) 1,8- diazabicycloundec-7-ene (1.1 equiv), isoprene (20 equiv), Me2AlCl (3.5 equiv), PhMe, –78 ˚C to –10 ˚C 52% 21 + 12% 22; d) magnesium (8.0 equiv), titanium tetrachloride (2.0 equiv), THF/CH2Cl2, 0 ˚C to r.t., 43%; e) selenium dioxide (1.5 equiv), dioxane, 80 ˚C, 42%; f) 2-iodoxybenzoic acid (2.0 equiv), DMSO, r.t., 87%; g) methyllithium (4.5 equiv), cerium(III) chloride (5.0 equiv), THF, –78 ˚C to 0 ˚C; i) thionyl chloride (2.1 equiv), triethylamine (5.4 equiv), CH2Cl2, –78 ˚C to 0 ˚C, 78% combined.

This article is protected by copyright. All rights reserved COMMUNICATION reagents. We thus turned our attention to conditions successful biosynthesis of aplydactone, in particular whether or not at methylenating highly hindered substrates[20] utilizing enzymatic machinery is necessary in its biogenesis. It is worth dichloromethane as a methylene equivalent in combination with noting that photochemical transformations, specifically those 0 TiCl4 and Mg . These conditions were sufficient to convert 21 utilizing sunlight, have been directly implicated in the into the doubly unsaturated spirocycle 9 in 43% yield. An biosynthesis of marine natural products.[25] exhaustive investigation of known olefination conditions did not The enantioselective total synthesis of (–)-- and (–)-ent- provide superior results. Surprisingly, attempts to convert -bromochamigrene, (–)-dactylone, and (+)-aplydactone was epimeric spiroketone 22 to (–)-ent--bromochamigrene (4) enabled by the gram-scale enantiospecific solvolytic cyclization using the conditions listed above resulted in diminished yields of an enantioenriched bromochloride. Access to this compared to its corresponding isomer. However, a two-step interhalogenated motif was enabled by the highly chemo-, protocol via the addition of methylcerium dichloride[7] followed diastereo-, and enantioselective Schiff base catalyzed by dehydration in the presence of thionyl chloride afforded ()- bromochlorination of allylic alcohol 13. This work highlights a - and ()-ent--bromochamigrene as a 1.5:1 mixture in 78% highly general approach to the halogenated chamigrene yield. Conversion of spirodiene 9 to dactylone 7 called for a sesquiterpenes and we anticipate that it will find use in the selective allylic oxidation of the methylene at C4 to the ketone synthesis of additional members of this class. Studies along oxidation state. Unfortunately, conditions to directly affect this those lines as well as a comprehensive investigation into the transformation[21] failed to selectively oxidize the allylic solvolytic cyclization of enantioenriched dihalides are in methylene at C4 over C2. Selenium dioxide[22] efficiently progress and will be reported in due course. produced the C4 allylic alcohol, which was readily oxidized to the corresponding enone with IBX, completing the first synthesis of (–)-dactylone 7. Cognizant of the reported failed attempts of the isolation team to convert dactylone 7 to Acknowledgements aplydactone 8 under long-term UV irradiation,[9] we nevertheless subjected dactylone 7 to known enone [2+2] We are grateful to Dr. A. Oliver (University of Notre Dame) for conditions under irradiation with 350 nm light. To our delight, X-ray crystallographic analysis and Dr. S. Lynch (Stanford dactylone 7 underwent clean conversion to aplydactone 8 (see University) for assistance with NMR spectroscopy. This work Table 1 for X-ray structure) over a period of 36 hours, which we was supported by Stanford University, the National Institutes of were able to isolate in near-quantitative yield (98%) after silica gel chromatography.[23] Health (R01 GM114061), and the National Science Foundation (DGE-114747 GRF to AJB).

Keywords: asymmetric synthesis • halogenation • natural products • solvolysis • terpenes

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Alexander J. Burckle, Vasil H. Vasilev, and Prof. Dr. Noah Z. Burns

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A Unified Approach for the Enantioselective Synthesis of the Brominated Chamigrene Text for Table of Contents Sesquiterpenes

Dihalides Light the Way: A highly general approach to the brominated chamigrene sesquiterpenes has been realized via a stereospecific bromopolyene cyclization of an enantioenriched bromochloride. The total synthesis of (+)-aplydactone has been accomplished for the first time via an intramolecular [2+2] cycloaddition.